Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02652975 |
| Other study ID # |
ABCDE_AUH |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
September 2015 |
| Est. completion date |
June 2018 |
Study information
| Verified date |
May 2017 |
| Source |
University of Aarhus |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Several cytotoxic regimens are related to endothelial cell damage and vascular toxicity.
Endothelial dysfunction is implicated in the pathogenesis of all known cardiovascular
diseases (CVD) and closely related to the metabolic syndrome. Both CVD and diabetes
contributes importantly to total mortality and to breast cancer (BC) specific mortality.
In the epidemiological part of the project, the investigators will determine the prevalence
and incidence of cardiovascular and metabolic morbidity/mortality in early BC patients
compared to the Danish background population.
In the clinical part, the investigators will study the changes of endothelial function and
metabolic parameters in BC patients receiving chemotherapy.
With increasing number of BC survivors, long-term consequences of curative cancer treatment
should be studied. The investigators hypothesize that cytotoxic therapy worsens metabolic
parameters possibly through endothelial dysfunction. If this is true, the next step will be
to evaluate how strict metabolic control will affect prognosis.
Description:
1. Background
During the past 30 years, survival of breast cancer patients has improved substantially
due to earlier diagnosis, improved surgical techniques, introduction of new combination
of chemotherapy, new hormonal treatment, introduction of targeted treatment, and
refinement of radiation techniques. With increasing number of cancer survivors, which in
part are reached by more aggressive treatment, more attention is presently being drawn
to long-term consequences of curative cancer treatment.
Comorbidity among breast cancer patients has been thoroughly studied over the past
years. Previous research has however, primarily focused on prevalence of comorbidity at
the time of the cancer diagnosis (manifest comorbidity) and less attention has been paid
to studying latent comorbidity developing after the diagnosis, which can be a result of
the treatment. Furthermore it is not known if the incidence of this later developed
comorbidity is different in breast cancer patients compared to the general population.
Additionally, most studies do not address specific diseases but focus on comorbidity as
such. Emerging evidence, however, indicates that cardiovascular disease (CVD)
(encompassing cerebrovascular disease manifested by stroke and TCI and coronary heart
disease manifested by infarction, arrhythmias, heart failure and sudden death) and
diabetes may play a pivotal role, because it contributes importantly both to total
mortality and to breast cancer specific mortality among breast cancer survivors.
Comorbidity at breast cancer diagnosis is an independent adverse prognostic factor. In
Denmark, comorbidity was present in 26% of breast cancer patients diagnosed 2006-2008,
and the presence of comorbidity increased the risk of dying from breast cancer as well
as from other causes with adjusted hazard ratios for all-cause mortality of 1.45 and
breast cancer-specific mortality 1.30. Most studies have, however, used a summary
measure of comorbidity such as the Charlson Comorbidity Index Score, and only few
studies have assessed the individual effects of specific comorbidities on the mortality
among breast cancer patients. These few studies universally demonstrate that CVD and
diabetes are associated with decreased overall survival. Thus, Patnaik et al showed that
among breast cancer patients, women with the following comorbidities were more likely to
die as a result of other causes: CVD (59.2%), COPD (52.2%), diabetes (47.8%) and
previous cancer (43.8%) Fully adjusted relative hazards of the effects of comorbidities
on breast cancer-specific mortality was 1.24 for CVD and 1.10 for diabetes, and among
the total study population of breast cancer patients, CVD was the primary cause of death
(15.9%), followed closely by breast cancer (15.1%). In a meta-analysis of studies of
overall survival in breast cancer patients with preexisting diabetes, Barone et al found
that preexisting diabetes was associated with an increased mortality with a hazard rate
(HR) of 1.61; (95% CI, 1.46-1.78).
Metabolic syndrome (MS) is a cluster of disorders including hypertension, type II
diabetes, dyslipidemia and obesity, and certain aspects of the MS are well described in
relation to breast cancer. It has been shown that obesity is associated with an
increased risk of developing breast cancer among postmenopausal women, obese patients
present with more advanced cancers, and women who are overweight or obese at the time of
breast cancer diagnosis or gain weight after diagnosis are at increased risk of cancer
recurrence and death compared with leaner women. One study have shown that the effects
of adjuvant therapy is less in obese breast cancer patients. An association between
diabetes and breast cancer has also been observed. Other components of the MS, including
low HDL-cholesterol, high triglycerides, hypertension, and serum testosterone are,
however, less well described, but may be associated with an increased breast cancer risk
and a worse breast cancer prognosis. A recent study showed that patients with MS present
with more aggressive tumors. In patients with metastatic disease, response to
chemotherapy appears to be inferior when the patient is diagnosed with MS, as well.
Emerging evidence suggest that the MS may be quite prevalent among patients with breast
cancer.
In our study the metabolic syndrome will be defined in accordance with the definition of
the National Cholesterol Education Program (NCEP)/Adult Treatment Panel III (ATPIII). A
diabetic FPG level is defined as FPG >7 mmol/l; impaired fasting glycemia is defined as
FPG between 6.1 and 7.0 mmol/l according to World Health Organization criteria.
Endothelial cells line the internal lumen of all the vasculature and serve as an
interface between circulating blood and vascular smooth muscle cells (VSMCs). Apart from
being the key participant during the process of angiogenesis, these dynamic structures
can actively regulate basal vascular tone and vascular reactivity in physiological and
pathological conditions. They respond to mechanical forces and neurohumoral mediators by
releasing a variety of relaxing and contracting factors such as nitric oxide (NO) and
prostacyclin. The balance between the vasodilatation and vasoconstriction is maintained
by the endothelium, and the disruption of this balance leads to endothelial dysfunction
and causes damage to the arterial wall. Endothelial cells are also responsible for the
maintenance of blood fluidity and restoration of vessel wall integrity (when injured) to
avoid bleeding. Endothelial cell-derived factors are also critical mediators of VSMC
growth and inflammation.
Several cytotoxic regimens have been shown to cause endothelial cell damage and vascular
toxicity by various mechanisms. Thus, anthracyclines and taxanes (which forms the
cornerstone of breast cancer treatment) together with cytotoxics as alkylating agents,
bleomycin, vinca alkaloids and antimetabolites have been associated with endothelial
cell apoptosis, oxidative stress, inflammation, coagulation disorders/thrombotic state,
endothelial cell proliferation-migration, effects on VEGF, and impaired
endothelial-dependent vasodilation in vitro and in vivo, although the exact mechanisms
are not known. Changes in endothelial function hasten the development of micro- and
macro-angiopathy and endothelial dysfunction is an important surrogate marker of
atherosclerotic activity. Endothelial dysfunction has been implicated in the
pathogenesis and clinical course of all known cardiovascular diseases and is associated
with future risk of adverse cardiovascular events.
Endothelial dysfunction is closely related to the MS, and a deficiency of
endothelial-derived NO is believed to be the primary defect that links insulin
resistance and endothelial dysfunction. It is not known whether worsening of endothelial
dysfunction aggravates elements of the MS.
2. Objective
The aim of this research program is to study the changes of endothelial function and
metabolic parameters in patients receiving chemotherapy for early stage breast cancer, and to
compare these parameters with healthy age matched controls.
Our theory is that cytotoxic therapy can induce endothelial cell damage and vascular toxicity
causing endothelial dysfunction. The investigators believe that endothelial dysfunction is a
mediator in the MS and predisposes to later cardiovascular disease, thus rendering patients
receiving cytotoxic therapy at risk of these conditions.
The investigators hypothesize that:
1. Cytotoxic therapy induces endothelial dysfunction in predisposed early breast cancer
patients.
2. Metabolic syndrome may be aggravated by cytotoxic therapy, possibly through worsening of
endothelial dysfunction.
3. Treatment of early breast cancer (chemotherapy, antihormonal therapy and/or trastuzumab)
aggravates preexisting CVD and/or metabolic disease and may induce the metabolic
syndrome.
3) Methods
The study is a clinical case-control study with the inclusion of 90 patients divided into 3
groups as stated below. 30 healthy women with the same age will participate as controls
(group 4).
Group 1: Newly diagnosed patients with early breast cancer. Investigated immediately prior to
start of adjuvant therapy.
Group 2: Early breast cancer patients, who have received standard treatment. Investigated
immediately after completion of adjuvant chemotherapy.
Group 3: Early breast cancer patients, who have received standard treatment. Investigated 1
year after completed chemotherapy.
Group 4: Healthy, age-matched controls. Controls will be recruited from an internet resource
(www.forsoegsperson.dk):
The test program will consist of the following investigations:
1. To characterize endothelial function in vivo the effect of vasodilatating substances is
measured in the forearm circuit. The substances is administered via a thin catheter
placed in the Brachial artery near the elbow in local anesthesia. Once the vessels
dilate, the blood flow in the forearm will increase and the flow change is a measure of
the vasodilatory capacity of that substance. The change is measured with classical
venous occlusion plethysmography. The method described is established at Aarhus
University Hospital and has been used for several decades to illustrate the effect of
vasoactive drugs on the human circulation, meaning it is a proven and well documented
method.
2. Applanation tonometry (pulse wave velocity and central blood pressure/arterial
stiffness): The central blood pressure and the augmentation index is estimated from the
shape of the radial pulse wave measured with a tonometer.
Pulse wave velocity (PWV) is calculated from the average difference between the pulse
pressure wave measured with a tonometer and the R in an ECG recorded simultaneously.
3. Medical history: A full medical history including use of medication is obtained from
every subject. Age, smoking status and concurrent medication. For patients tumor
characteristics and anticancer treatment will also be described.
4. Clinical examination: A regular objective examination is performed including weight,
height (BMI) and measurements of hip and waist circumference.
5. Measurements of body composition: Total body fat and fat free mass is measured by Dual
Energy X-ray Absorptiometry (DEXA).
6. Electrocardiography: A conventional 12 lead surface electrocardiogram is recorded.
7. 24 hour blood pressure measurement
8. Laboratory tests: Fasting blood tests are drawn from an antecubital placed catheter
(albumin, ALAT/ASAT, alkaline phosphatase, bilirubin, gammaglutamyl transferase,
coagulation factors, red and white blood cells, creatinin, potassium, sodium, fasting
lipids, fasting glucose, hemoglobin A1C, insulin, sex hormones, von Willebrand factor,
low grade inflammation markers, DNA and RNA for later analyses, including relevant
coding genes).
Further more urine samples to determine possible systemic impact of cardiovascular
disease.
The investigators will create a biobank containing urine and blood samples from
participants for future research, provided that the participant gives her permission.
Responsibility for the biobank lies with the project responsible physician, Anders Bonde
Jensen.
9. To characterize the overall risk of cardiovascular death within 10 years, the
investigators will use a well- established and validated method called SCORE using age,
gender, smoking status, systolic blood pressure and plasma cholesterol for risk
stratification.
10. Every premenopausal woman will be asked about the possibility of her being pregnant. In
case of doubt the investigators will do a pregnancy test (urine hcg)
